TY  - JOUR
AU  - He, Lixiazi
AU  - Arnold, Christian
AU  - Thoma, Judith
AU  - Rohde, Christian
AU  - Kholmatov, Maksim
AU  - Garg, Swati
AU  - Hsiao, Cheng-Chih
AU  - Viol, Linda
AU  - Zhang, Kaiqing
AU  - Sun, Rui
AU  - Schmidt, Christina
AU  - Janssen, Maike
AU  - MacRae, Tara
AU  - Huber, Karin
AU  - Thiede, Christian
AU  - Hébert, Josée
AU  - Sauvageau, Guy
AU  - Spratte, Julia
AU  - Fluhr, Herbert
AU  - Aust, Gabriela
AU  - Müller-Tidow, Carsten
AU  - Niehrs, Christof
AU  - Pereira, Gislene
AU  - Hamann, Jörg
AU  - Tanaka, Motomu
AU  - Zaugg, Judith B
AU  - Pabst, Caroline
TI  - CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.
JO  - EMBO molecular medicine
VL  - 14
IS  - 4
SN  - 1715-4684
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2022-00435
SP  - e14990
PY  - 2022
N1  - DKFZ-ZMBH Alliance / 2022 Apr 7;14(4):e14990
AB  - The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56+ LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56+ CD34+ fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease.
KW  - AML (Other)
KW  - CDK7 inhibition (Other)
KW  - GPR56 (Other)
KW  - leukemia stem cell (Other)
KW  - self-renewal (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35253392
DO  - DOI:10.15252/emmm.202114990
UR  - https://inrepo02.dkfz.de/record/179057
ER  -